Pharmaceutical formulations for the treatment and prevention of trauma-induced neuropathology and neurodegeneration

ABSTRACT

Novel multi-component formulations, procedures and methods for use in treating neuropathology and neurodegeneration incident to trauma are provided. Multi-component formulations of the invention comprise biologically active forms of any two, any three, or all four of at least one neurosteroid or neuroactive steroid, such as progesterone or synthetic progestin, at least one anti-epileptic or anticonvulsant, such as gabapentin, pregabalin or valproic acid, at least one NK-1 receptor antagonist, such as aprepitant, casopitant or vestipitant, at least one lithium-containing or lithium-related drug. The provided formulations are configured or adapted to prevent or reduce the incidence and severity of neurological damage caused by trauma, or the risk of such damage. Formulations, procedures and methods of the invention advantageously effect both neuroprotective actions to prevent or reduce secondary injuries, and neurotrophic actions to repair and restore cells and tissues affected by the trauma, and are especially useful in treating injury or trauma to nerve cells, to neural support cells and to neural support tissues.

RELATED APPLICATION AND PRIORITY

This Utility Patent Application claims the priority and benefit ofcommonly owned U.S. Provisional Patent Application Ser. No. 61/750,745of James L. Henry, as filed 9 Jan. 2013, and as entitled “Formulations,Methods And Procedures For Reducing Or Preventing The Development Or TheRisk Of Development Of Neuropathology As A Result Of Traumatic Injury,”which provisional patent application is hereby incorporated by referencein its entirety into the present patent application. Also herebyincorporated by reference in their entireties are each of the referencescited herein, as well as those cited in Provisional Patent ApplicationSer. No. 61/750,745.

FIELD OF THE INVENTION

The presently disclosed invention and many particular inventionembodiments relate to multiple-component formulations, the use of suchformulations, and to methods, procedures and combinations thereof toprevent or reduce, or to reduce the risk of, the damage that canotherwise lead to numerous types of neuropathology as a result oftrauma.

SUMMARY OF THE INVENTION

Anticonvulsant/antiepileptic compounds suitable for use as components ofinvention embodiments include, but not exclusively, one or more from thegroup comprising gabapentin, pregabalin, barbiturates (such asphenobarbital, methylphenobarbital, metharbital, barbexaclone and othercentral nervous system depressants), benzodiazepines (such as clozepam,clonazepam, chlorazepate, diazepam, midazolam, lorazepam, and otherhypnotic, anxiolytic, anticonvulsant, amnesic compounds), bromides (suchas potassium bromide,) carbamates (such as felbamate, fluorofelbamate),carboxamides (such as carbamazepine, oxcarbazepeine, eslicarbazepineacetate), fatty acids (such as valproic acid, sodium valproate,divalproex sodium, vigabatrin, progabide, sec-butyl-propylacetamide),fructose derivatives (such as topiramate), hydantoins (such as ethotoin,phenytoin, mephenytoin, fosphentoin), oxazolidinediones (such asparamethadione, trimethadione, ethadione), propionates (such asbeclamide), pyrimidinediones (such as primidone), pyrrolidines (such asrivaracetam, levetiracetam, seletracetam), succinimides (such asethosuximide, phensuximide, mesuximide), sulfonamides (such asacetazolamide, sultiame, methazolamide, zonisamide), triazines (such aslamotrigine), ureas (such as pheneturide, phenacemide) and valproyamides(such as valpromide, valoctamide) and others known and unknown, as wellas any homolog or derivative or compound acting on or through areceptor, an enzyme or other mechanism upon which ananticonvulsive/antiepileptic can act, as well as any compound acting onor through mechanisms that would modify or affect in any way pathways orprocesses affected by one or more anticonvulsant/antiepilepticcompounds, as well as any related slow-release compound.

Neurosteroid/neuroactive steroid compounds suitable for use ascomponents of invention embodiments include, but not exclusively, one ormore from the group comprising progesterone, progesterone prodrugs,progesterone derivatives, progesterone analogs, and other progesteronecompounds such as but not exclusive to medroxyprogesterone acetate,megestrol acetate, 17a-hydroxyprogesterone, 5a-dihydroxyprogesterone,3a,5a-trihydroxyprogesterone, 14b-hydroxy progesterone,17a-hydroxyprogesterone caproate,16-methyl-17-benzoyloxypregnen-4-en-3,20-dione,hydroxyprogesterone-3-O-carboxymethyloxime,21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone,17-p-bromophenyl-carbamoyloxypregn-4-ene-3,20-dione,17-phenylcarbamoyl-oxypregn-4-ene-3,20-dione, 4-pregnene-3,20-dione,6,19-methanoprogesterone, 16,17-cyclohexano-4,5-dihydroprogesterone,nepapakistamine, vaganine D, Crinone, 18-oxo-18-vinylprogesterone,16,17-cyclopropanoprogesterone, caproxyprogesterone,21-hydroxy-6,19-oxidoprogesterone,17-acetoxy-9-fluoro-6-methylprogesterone, ZK 136798,3,17-dihydroxy-7-(4-methoxyphenyl)-androst-5-ene, 3,17-diacetate,progesterone-11HS-horseradish peroxidase,21-hydroxy-11,19-oxidopregn-4-ene-3,20-dione,21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione, 4-cyanoprogesterone,11,19-oxidoprogesterone, 6-fluoroprogesterone,2-hydroxy-4-pregnene-3,20-dione, progesterone-3-(O-carboxymethyloxime)-horseradish peroxidase, progesterone-11-hemisuccinyl-bovine serumalbumin, pentarane B, pentarane A, progesterone 6-hemimaleate,progesterone 6-hemisuccinate, 7-(carboxyethylthio)progesterone,progesterone 3-(O-carboxymethyl)oxime-bovine serum albumin,18-ethynylprogesterone, 18-vinylprogesterone,6-methylprogesteron-17-pivalate, progesterone-11-bovine serum albumin,allylestriol, progesterone-3-ethanolimine,3,20-dioxopregn-4-ene-18′-carboxaldehyde cyclic18′-(1,2-ethandiylmercaptal), 18-ethylenedithioprogesterone,17-acetoxy-6,16-dimethylene-4-pregnene-3,20-dione,17-hydroxy-6-dehydroprogesterone,2′-methyl-16,17-cyclohexaneprogesterone, 21,21-dichloroprogesterone,hydroxyprogesterone hemisuccinate bovine serum albumintetramethylrhodamine isothiocyanate,11-progesteryl-2-carboxymethyltyramine-4-(10-methyl)acridinium-9-carboxylate,progesterone 12-succinyltyrosine methyl ester, progesterone11-succinyltyrosine methyl ester,11-progesteryl-2-succinoyltyramine-4-(10-methyl)acridinium-9-carboxylate,2-hydroxymethyleneprogesterone, 2-cyanoprogesterone,17-(phenylseleno)progesterone, 21-(phenylseleno)progesterone and othersknown and unknown, and include other neurosteroids or neuroactivesteroids such as, but not exclusive to prednisolone, methylprednisolone,alphaxolone, alphadolone, hydroxydone, minaxolone, ganaxolone,deoxycorticosterone, 3 alpha-hydroxy-5-alpha-pregnan-one(allopregnanolone), 3 alpha,21-dihydroxy-5 alpha-pregnan-20-one(allotetrahydro), as well as metabolites of neurosteroids andneuroactive steroids, and including any corticoid, glucocorticoid,estrogen compound or any such compound acting on or through aprogesterone, corticosteroid, glucocorticoid, estrogen or otherneurosteroid receptor or through any other mechanism upon whichprogesterone, a corticosteroid, a glucocorticoid, an estrogen or otherneurosteroid does or can act, as well as any homolog or derivative orcompound acting on or through mechanisms that would modify, modulate oraffect in any way pathways or processes affected by progesterone,estrogen or any neurosteroid, as well as any related slow-releasecompound.

NK-1 receptor antagonist compounds suitable for use as components ofinvention embodiments include, but not exclusively, any biologicallyactive compound of one or more from the group comprising aprepitant,fosaprepitant, casopitant, maropitant, vestipitant, CP-99,994,CP-122,721, MK 869, LY 303870, RPR 67580, RPR 100893, L 758298, L365260, L 733060, GR 205171, CGP 49823, CJ 11974, and others known andunknown, and any compound acting on or through the NK-1 receptor or anyother mechanism that involves activation or involvement of the NK-1receptor or its synthesis, and other chemical entities known andunknown, including any ligand or compound acting on or through an NK-1receptor or other mechanism upon which substance P, an endogenous ligandfor the NK-1 receptor, does or can act, as well as any compound actingon or through mechanisms that would modify or affect in any way pathwaysor processes affected by substance P or the NK-1 receptor, as well asany related slow-release compound. Further, in view of the evidence thatsome ligands and compounds can act through or by NK-2 or NK-3 receptors,any ligand or homolog or derivative or compound acting on or through anNK-1 or NK-2 or NK-3 receptor, including receptor isoforms, or relatedmechanism as well as any ligand that occupies, activates or deactivatesthese receptors, is included in the presently disclosed technology.

Lithium-related/lithium-containing compounds suitable for use ascomponents of invention embodiments include, but not exclusively, anybiologically active compound of one or more from the group comprisinglithium citrate, lithium carbonate, lithium chloride, lithium bromatumand others known and unknown, as well as any compound acting on orthrough a lithium receptor or other mechanism upon which lithium does orcan act, as well as any homolog or derivative or compound acting on orthrough mechanisms that would modify or affect in any way pathways orprocesses affected by lithium, as well as any related slow-releasecompound.

Numerous compounds can be administered to a subject in any combinationor permutation of these classes of compound to practice this inventionaimed to reduce or prevent the development or the risk of development ofneuropathology as a result of traumatic injury to a subject byadministering to a subject in need thereof a multiplicity of compoundsby such combinations of any two, any three or any four compounds fromthe classes of compounds comprising anticonvulsants/antiepileptics,neurosteroids/neuroactive steroids, NK-1 receptor antagonists andlithium-related/lithium-containing compounds. These combinations ofabove said compounds can be given by various routes of administration totreat any injury or damage that has resulted, will result or may resultfrom trauma, and that injury or damage can be to any nerve cell or nervecells, to any neural support cell as described herein, or to any neuralsupport tissue as described herein. Injury or damage can be to thebrain, the brain stem, the cerebellum, the spinal cord, the entericnervous system and the peripheral nervous system or any other nervecell. A subject in need of invention embodiments can be an individualwho is at risk of injury or damage, an individual who is about toexperience an event that has the potential to cause traumatic damage orinjury, or an individual who has experienced a trauma as describedherein.

The presently disclosed technology includes formulations, methods andprocedures aimed at reducing or preventing the development, or the riskof development, of neuropathology as a result of traumatic injury.Embodiments of the invention address unmet or unsolved medical needsincluding brain injury, central nervous system ischemia, spinal cordinjury, enteric nervous system injury, peripheral nerve injury and anyother injury that can include or affect nerve cells, neural supportcells or neural support tissues. These unmet or unsolved medical needsshare the commonness of the potential for life-long adverse healthconditions or disability. They also share the commonness of the void incurrent medical interventions to reduce or prevent these adverse healthconditions or disability.

These conditions also share similar, common or overlapping mechanisms ofthe secondary injury that develops following a primary injury or trauma,common mechanisms that trigger or lead to this secondary injury andcommon possible therapeutic targets for inhibiting or promoting thecascades of mechanisms triggered by a primary injury. As such mechanismsare triggered immediately by trauma while others downstream in thecascades of biochemical and metabolic pathways are engaged at differenttimes following trauma, it is necessary to administer components of theformulation through the hours, days and in some cases the weeksfollowing trauma, with immediate initiation of treatment of paramountimportance for the preventive measures to arrest the degenerativecascades and to promote the restorative cascades, as well ascontinuation of practice according to need.

DETAILED DESCRIPTION OF THE INVENTION

In accordance with some of the objects of the invention, formulationsfor use in one or more treatments, procedures and methods to prevent thedevelopment, or the risk of development, of neuropathology andneurodegeneration sequelae associated with or caused by trauma orneurotrauma to a subject in need, or for the amelioration of the effectscaused by trauma to a subject in need, are provided.

In one advantageous aspect, the present technology presents manyembodiments of formulations comprising, or consisting essentially of,any two or any three or all four biologically active compounds inamounts that are pharmaceutically effective for each compound,respectively, when used in combination with the other biologicallyactive compounds, the compounds being selected from a pharmaceuticallyeffective amount of any two or any three or all four of A) at least onebiologically active compound selected from the group comprisinganticonvulsants and antiepileptics; B) at least one biologically activecompound selected from the group comprising neurosteroids andneuroactive steroids; C) at least one biologically active compoundselected from the group comprising NK-1 receptor antagonists; and D) atleast one biologically active compound selected from the groupcomprising lithium-containing and lithium-related compounds.

As one of skill in the art will appreciate, many embodiments of thepresent formulations suitable for use in methods or procedures fortreatment of such neuropathology and neurodegeneration sequelaeassociated with or caused by trauma or neurotrauma are within the scopeand spirit of the present technology. Such formulations include, asexamples, wherein the at least one anticonvulsant or antiepileptic agentis one or more from the group consisting of gabapentin, pregabalin,barbiturates (such as phenobarbital, methylphenobarbital, metharbital,barbexaclone and other central nervous system depressants),benzodiazepines (such as clozepam, clonazepam, chlorazepate, diazepam,midazolam, lorazepam, and other hypnotic, anxiolytic, anticonvulsant,amnesic compounds), bromides (such as potassium bromide), carbamates(such as felbamate, fluorofelbamate), carboxamides (such ascarbamazepine, oxcarbazepine, eslicarbazepine acetate), fatty acids(such as valproic acid, sodium valproate, divalproex sodium, vigabatrin,progabide, sec-butyl-propylacetamide), fructose derivatives (such astopiramate), hydantoins (such as ethotoin, phenytoin, mephenytoin,fosphentoin), oxazolidinediones (such as paramethadione, trimethadione,ethadione), propionates (such as beclamide), pyrimidinediones (such asprimidone), pyrrolidines (such as rivaracetam, levetiracetam,seletracetam), succinimides (such as ethosuximide, phensuximide,mesuximide), sulfonamides (such as acetazolamide, sultiame,methazolamide, zonisamide), triazines (such as lamotrigine), ureas (suchas pheneturide, phenacemide) and valproyamides (such as valpromide,valoctamide) and others known and unknown, as well as any homolog orderivative or compound acting on or through a receptor, an enzyme orother mechanism upon which an anticonvulsive/antiepileptic can act, aswell as any compound acting on or through mechanisms that would modifyor affect in any way pathways or processes affected by one or moreanticonvulsant/antiepileptic compounds, as well as any relatedslow-release compound.

In a similar advantageous combinatorial aspect, the present technologyprovides many embodiments of formulations comprising any two, or anythree, or all four, biologically active compounds in amounts that arepharmaceutically effective for each compound, respectively, when used incombination with the other biologically active compounds, wherein the atleast one neurosteroid or neuroactive steroid is one or more compoundsselected from the group consisting of progesterone, progesteroneprodrugs, progesterone derivatives, progesterone analogues, and otherprogesterone compounds such as but not exclusive to medroxyprogesteroneacetate, megestrol acetate, 17alpha-hydroxyprogesterone,5alpha-dihydroxyprogesterone, 3alpha,5alpha-trihydroxyprogesterone,14b-hydroxy progesterone, 17alpha-hydroxyprogesterone caproate,16-methyl-17-benzoyloxypregnen-4-en-3,20-dione,hydroxyprogesterone-3-O-carboxymethyloxime,21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone,17-p-bromophenyl-carbamoyloxy-pregn-4-ene-3,20-dione,17-phenylcarbamoyl-oxypregn-4-ene-3,20-dione, 4-pregnene-3,20-dione,6,19-methanoprogesterone, 16,17-cyclohexano-4,5-dihydroprogesterone,nepapakistamine, vaganine D, Crinone, 18-oxo-18-vinylprogesterone,16,17-cyclopropanoprogesterone, caproxyprogesterone,21-hydroxy-6,19-oxidoprogesterone,17-acetoxy-9-fluoro-6-methylprogesterone, ZK 136798,3,17-dihydroxy-7-(4-methoxyphenyl)-androst-5-ene, 3,17-diacetate,progesterone-11HS-horseradish peroxidase,21-hydroxy-11,19-oxidopregn-4-ene-3,20-dione,21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione, 4-cyanoprogesterone,11,19-oxidoprogesterone, 6-fluoroprogesterone,2-hydroxy-4-pregnene-3,20-dione, progesterone-3-(O-carboxymethyloxime)-horseradish peroxidase, progesterone-11-hemisuccinyl-bovine serumalbumin, pentarane B, pentarane A, progesterone 6-hemimaleate,progesterone 6-hemisuccinate, 7-(carboxyethylthio)progesterone,progesterone 3-(O-carboxy-methyl)oxime-bovine serum albumin,18-ethynylprogesterone, 18-vinylprogesterone,6-methylprogesteron-17-pivalate, progesterone-11-bovine serum albumin,allylestriol, progesterone-3-ethanolimine,3,20-dioxopregn-4-ene-18′-carboxaldehyde cyclic18′-(1,2-ethandiylmercaptal), 18-ethylenedithioprogesterone,17-acetoxy-6,16-dimethylene-4-pregnene-3,20-dione,17-hydroxy-6-dehydroprogesterone,2′-methyl-16,17-cyclohexaneprogesterone, 21,21-dichloroprogesterone,hydroxyprogesterone hemisuccinate bovine serum albumintetramethylrhodamine isothiocyanate,11-progesteryl-2-carboxymethyltyramine-4-(10-methyl)acridinium-9-carboxylate,progesterone 12-succinyltyrosine methyl ester, progesterone11-succinyltyrosine methyl ester,11-progesteryl-2-succinoyltyramine-4-(10-methyl)acridinium-9-carboxylate,2-hydroxymethyleneprogesterone, 2-cyanoprogesterone,17-(phenylseleno)progesterone, 21-(phenylseleno)progesterone and othersknown and unknown, and include other neurosteroids or neuroactivesteroids such as, but not exclusive to neuroactive progestagens(including but not limited to pregnenolone(3beta-hydroxypregn-5-en-20-one), 17α-hydroxypregnenolone, progesterone,17α-hydroxyprogesterone, dehydroepiandrosterone, androstenedione,deoxycorticosterone, 11-deoxycortisol, 3 alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), 3 alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydroDOC)), neuroactive androgens(including but not limited to androstenedione (the precursor of3alpha,5alpha-A, or androsterone), androsterone(5alpha-androstan-3alpha-ol-17-one; 3alpha,5alpha-A),5alpha-dihydrotestosterone (5alpha-DHT) and its metabolite5alpha-androstane-3alpha,17beta-diol (3alpha,5alpha-Adiol),3α,17β-dihydroxy-5α-androstane, 3α-hydroxy-5α-androstan-17-one,3α-hydroxy-5β-androstan-17-one, androst-5-ene-3β,17β-diol,3β,17α-dihydroxy-pregn-5-en-20-one (17α-hydroxy-pregnenolone),3β-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA),testosterone, androst-4-ene-3,17-dione (androstenedione), neuroactiveestrogens (including but not limited to estradiol, 17β-estradiol (βE2),17α-estradiol (αE2), estrone (E1) and estriol (E3), and phytoestrogens),neuroactive glucocorticoids (including but not limited to prednisolone),other neuroactive steroids metabolically downstream from these principalneuroactive steroids including but not limited to allopregnanolone,allotetrahydrodeoxycorticosterone (THDOC), and dehydroepiandrosterone(DHEA), additional neuroactive steroids including other derivatives suchas estradiol benzoate, neurosteroids and neuroactive steroids including,but not limited to, prednisolone, methylprednisolone, alphaxalone,alphadolone, hydroxydone, minaxolone, ganaxolone, deoxycorticosterone, 3alpha-hydroxy-5-alpha-pregnan-one (allopregnanolone), 3alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydro), as well asmetabolites of neurosteroids and neuroactive steroids, and including anycorticoid, glucocorticoid, estrogen, estrogen compound, androgen orandrogen compound or any such compound acting on or through aprogesterone, corticosteroid, glucocorticoid, estrogen, androgen orother neurosteroid or neuroactive steroid receptor or through any othermechanism upon which progesterone, a corticosteroid, a glucocorticoid,an estrogen or other neurosteroid or neuroactive steroid does or canact, as well as any homolog or derivative or compound acting on orthrough mechanisms that would modify, modulate or affect in any waypathways or processes affected by progesterone, estrogen or anyneurosteroid or neuroactive steroid, as well as any related slow-releasecompound.

In yet another advantageous combinatorial aspect, the present technologyalso provides many embodiments of formulations comprising any two, orany three, or all four, biologically active compounds in amounts thatare pharmaceutically effective for each compound, respectively, whenused in combination with the other biologically active compounds,wherein the at least one NK-1 receptor antagonist is one or more fromthe group consisting of aprepitant, fosaprepitant, casopitant,maropitant, vestipitant, CP-99,994, CP-122,721, MK 869, LY 303870, RPR67580, RPR 100893, L 758298, L 365260, L 733060, GR 205171, CGP 49823,CJ 11974, and others known and unknown, and any compound acting on orthrough the NK-1 receptor or any other mechanism that involvesactivation or involvement of the NK-1 receptor or its synthesis, andother chemical entities known and unknown, including any ligand orcompound acting on or through an NK-1 receptor or other mechanism uponwhich substance P, an endogenous ligand for the NK-1 receptor, does orcan act, as well as any compound acting on or through mechanisms thatwould modify or affect in any way pathways or processes affected bysubstance P or the NK-1 receptor, as well as any related slow-releasecompound. Further, in view of the evidence that some ligands andcompounds can act through or by NK-2 or NK-3 receptors, any ligand orhomolog or derivative or compound acting on or through an NK-1 or NK-2or NK-3 receptor, including receptor isoforms, or related mechanism aswell as any ligand that occupies, activates or deactivates thesereceptors, is included in the presently disclosed technology.

In yet an additional advantageous and combinatorial aspect, the manyembodiments of the present technology include many embodiments offormulations comprising any two or any three or all four biologicallyactive compounds in amounts that are pharmaceutically effective for eachcompound, respectively, when used in combination with the otherbiologically active compounds, wherein the at least onelithium-containing/lithium-related agent is one or more from the groupconsisting of lithium carbonate, lithium citrate, lithium chloride,lithium bromatum and others known and unknown, as well as any compoundacting on or through a lithium receptor or other mechanism upon whichlithium does or can act, as well as any homolog or derivative orcompound acting on or through mechanisms that would modify or affect inany way pathways or processes affected by lithium, as well as anyrelated slow-release compound.

Examples of the many embodiments of formulations, methods and proceduresof the present technology are many. These include wherein theformulation consists of any two, or any three, or all four, of theanticonvulsants or antiepileptics, the neurosteroids or neuroactivesteroids, the NK-1 receptor antagonists and the lithium-containing orlithium-related compounds, and wherein the formulation is formulated, oradapted and arranged, for administration within 12 hours after thetrauma.

Such examples also include wherein the formulation consists essentiallyof any two, or any three, or all four, of the anticonvulsants orantiepileptics, the neurosteroids or neuroactive steroids, the NK-1receptor antagonists and the lithium-containing or lithium-relatedcompounds, and wherein the formulation is formulated, or adapted andarranged, to be first administered to a mammal in need thereof, within24 hours after the trauma.

In a similar aspect, the present technology includes formulationsconsisting essentially of any two, or any three, or all four, of theanticonvulsants or antiepileptics, the neurosteroids or neuroactivesteroids, the NK-1 receptor antagonists and the lithium-containing orlithium-related agents, and is formulated, or adapted and arranged, tobe first administered as a prophylactic measure within 90 minutes beforean expected or potential trauma, and wherein the formulation consistsessentially of any two, or any three, or all four, of the anticonvulsantor antiepileptic, the neurosteroid or neuroactive steroid, the NK-1receptor antagonist and the lithium-containing or lithium-related agentare formulated, or adapted and arranged, for administration within 24hours of the trauma.

The present technology also includes formulations consisting essentiallyof combinations wherein the anticonvulsants or antiepileptics, theneurosteroids or neuroactive steroids and the NK-1 receptor antagonistsare formulated for administration as a preventive measure within 90minutes before a possible trauma.

Moreover, embodiments of the present technology include wherein theformulation consists of any two or any three or all four of theanticonvulsant or antiepileptic, the neurosteroid or neuroactivesteroid, the NK-1 receptor antagonist and the lithium-containing orlithium-related agent, and is formulated for administration as aprecautionary measure within 90 minutes before a possible trauma.

Formulations of the present invention include also wherein theformulation comprises a single dosage unit, wherein the formulation isadapted and arranged for administration a plurality of times, such as insome type or types of sequences. These include wherein the formulationis adapted and arranged for administration in one or more dosage unitsper day, and wherein they are formulated for administration as one ormore of tablets, capsules, pills, lozenges or as one or more ingestibleor injectable solutions.

Consonant with the numerous embodiments of the invention areformulations adapted and arranged, or provided, as examples, foradministration via an oral, buccal, mucosal, parenteral, rectal,sub-cutaneous, transdermal, intravenous, intrathecal, intravaginal,nasal, nasal inhalation, pulmonary inhalation, iontophoresis through theskin, iontophoresis through mucosal or buccal membranes, dermal patch,epidural, intracranial, intrapharyngeal, sublingual, intra-articular,intramuscular or a subcutaneous route. Preferable subjects of thepresent technology include animals such as mammals, and more preferablyhumans.

As yet another advantage, the present formulations can be provided inone or more such forms adapted and arranged to be administered to, givento, or taken by, a subject, and may include other ingredients orsubstances such as excipients, buffers, penetration enhancers,stabilizers, absorption enhancers and carriers.

Also consonant with the present formulations are those wherein one ormore of the compounds is in the form of one or more of salts, prodrugs,hydrates, derivatives or metabolites of the compound itself, analogues,homologues, compounds acting on or through mechanisms that compounds canact on or through or compounds that modify, modulate or affect in anyway pathways or processes affected by compounds or formulations of theinvention.

As one of skill in the art will comprehend, the present technologyincludes numerous combinations, variations and permutations of the manyformulations provided within the spirit and scope of the presentdescription. Examples of embodiments of the present formulations includewherein the at least one anticonvulsant is gabapentin, in a form adaptedand arranged for administration to a mammal in need thereof, wherein theat least one anticonvulsant is pregabalin, in a form adapted andarranged for administration to a mammal in need thereof, and wherein theat least one anticonvulsant is valproic acid, in a form adapted andarranged for administration to a mammal in need thereof.

Exemplary formulation dosage ranges of the present technology include,as examples, wherein the gabapentin is provided in a range of from 5.0to 9,600 mg, wherein the pregabalin is provided in a range of from 0.5to 2,400 mg, wherein the valproic acid is provided in a range of from 25to 4,800 mg.

Examples of embodiments of the present formulations include also whereinthe at least one neurosteroid is progesterone, in a form adapted andarranged for administration to a mammal in need thereof, wherein the atleast one neurosteroid is methylprednisolone, in a form adapted andarranged for administration to a mammal in need thereof, and wherein theat least one neurosteroid is medroxyprogesterone acetate, in a formadapted and arranged for administration to a mammal in need thereof.

Exemplary formulation dosage ranges of the present technology includewherein the progesterone is provided in a range of from 0.05 to 1,200mg, the methylprednisolone, is provided in a range of from 0.02 to 500mg, wherein the medroxyprogesterone acetate, is provided in a range offrom 0.001 to 400 mg. Examples of embodiments of the presentformulations include also wherein the at least one NK-1 receptorantagonist is aprepitant, in a form adapted and arranged foradministration to a mammal in need thereof, wherein the at least oneNK-1 receptor antagonist is vestipitant, in a form adapted and arrangedfor administration to a mammal in need thereof; wherein the at least oneNK-1 receptor antagonist is casopitant, in a form adapted and arrangedfor administration to a mammal in need thereof.

Dosage ranges of the individual two, or three or four components of thepresent formulations include any which are effective, and especiallywherein the aprepitant, is provided in a range of from 0.05 to 750 mg,wherein the vestipitant, is provided in a range of from 0.001 to 200 mg,and wherein the casopitant, is provided in a range of from 0.005 to1,000 mg.

With respect to lithium-containing variations of the present invention,the present formulations include wherein the at least onelithium-containing compound is lithium carbonate, in a form adapted andarranged for administration to a mammal in need thereof; wherein the atleast one lithium-containing compound is lithium citrate, in a formadapted and arranged for administration to a mammal in need thereof, andwherein the at least one lithium-containing compound is lithiumchloride, in a form adapted and arranged for administration to a mammalin need thereof.

With respect to exemplary dosage ranges, embodiments of the presenttechnology include also wherein the lithium carbonate, is provided in arange of from 0.5 to 3,600 mg, wherein the lithium citrate, is providedin a range of from 0.01 to 2,400 mg, and wherein the lithium chloride,is provided in a range of from 3.0 to 3,600 mg.

The present technology includes also wherein embodiments of the presentformulations are adapted and arranged to treat one or more changes incellular or tissue structure, function or health, occurring in one ormore of the central nervous system, including the brain, the brainstem,the cerebellum and the spinal cord, and the periphery, including theenteric nervous system and the peripheral nervous system, and alsowherein they are adapted and arranged to treat one or more selected fromthe group comprising neuropathy, neuropathology, neurodegeneration andthe effects of trauma, and those governed by a balance ofneurotrophic/neuroprotective and neurodegenerative mechanisms.

The present technology includes also wherein embodiments of the presentformulations are adapted and arranged to treat one or more changesgoverned by neurotrophic and regenerative mechanisms that repair orregenerate nerve cells, neural support cells or neural support tissues.In a similar manner, the present technology includes also whereinembodiments of the present formulations are adapted and arranged totreat one or more changes governed by neurodegenerative mechanisms thatlead to secondary injury, neuropathology and neurodegeneration, and celldeath.

The presently disclosed technology also includes wherein embodiments ofthe present formulations are adapted and arranged to treatneuroprotective mechanisms to prevent or ameliorate neuropathology andneurodegeneration caused by or resulting from trauma.

In accordance with the broad applicability of the present formulations,methods and procedures, the present formulations can also be adapted andarranged to treat one or more selected from the group comprisingphysical trauma, chemical trauma, metabolic trauma, medically-relatedtrauma and other trauma, where injury or damage is to at least onenerve, at least one nerve cell, at least one neural support cell or atleast one neural support tissue, whether in the central nervous systemor in the periphery, and can also be adapted and arranged to treat oneor more from the group comprising brain changes resulting short-,medium- or long-term from trauma, including Alzheimer's disease,Parkinson's disease and other disorders where brain trauma is a riskfactor.

Similarly, formulations of the invention can be adapted and arranged totreat spinal cord trauma comprising one or more from the groupcomprising compression, vertebral collapse, cutting wounds, puncturewounds, crush wounds, surgical or medical intervention, and ischemiaresulting from loss of blood, insufficient circulation from stoppage orslowing of the heart, or surgical interruption of the blood supply tothe spinal cord.

Also, formulations of the invention also can be adapted and arranged totreat brain, brainstem and cerebellum trauma including one or more fromthe group comprising brain injury, ischemia of the central nervoussystem, physical trauma, chemical trauma, metabolic trauma, trauma fromsurgical or medical intervention or procedure and other trauma.

As one of skill in the art will appreciate, formulations of theinvention can be adapted and arranged to treat enteric nervous systemtrauma including injury to one or more from the group comprisingneurons, progenitor cells, glial cells and interstitial cells of Cajal,cells of Auerbach's myenteric plexus and Meissner's submucosal plexus,as well as neural support cells and neural support tissues, includingluminal, lamina propria and muscularis mucosal cells, as well asendothelial cells of the vasculature.

Similarly, formulations of the invention can be adapted and arranged totreat peripheral nerve trauma including one or more from the groupcomprising sensory nerves, motor nerves, autonomic nerves, nerve cells,neural support cells, such as Schwann cells, myelin cells, satellitecells, as well as neural support tissues such as the vasculature. Othertargets for the present formulations include those adapted and arrangedto treat following trauma as an emergency treatment of trauma as wouldbe in the case of unanticipated or accident-related trauma, taken assoon after trauma as possible that may prevent the development ofneuropathology and neurodegeneration or the risk of development ofneuropathology and neurodegeneration including such conditions as motorvehicle accidents, battlefield injuries, sports injuries, toxic chemicalspill and the like, where evidence informs that there is a risk ofdamage to brain, spinal cord or peripheral nerve. Emergency treatment toprevent secondary injury, neuropathology and neurodegeneration isdifferent from emergency treatment of trauma, where immediate steps aretaken to prevent further injury, to stop bleeding, to stabilize thevictim and to take life-saving steps.

The present formulations, methods and procedures can also be adapted andarranged to treat before trauma as would be in the case of anticipated,potential or purposeful trauma, taken as a pre-exposure prophylaxismeasure to reduce the risk of neuropathology in individuals who areabout to undergo procedures where there is a risk of trauma, includingsuch conditions as surgery, chemotherapy, radiation therapy and thelike, where evidence informs that there is a risk of damage to brain,brain stem, cerebellum, spinal cord, peripheral nerve and/or entericnerve cells, and wherein prophylaxis treatment for trauma is differentfrom pre- and post-surgical care, where steps are taken to ensure thepatient's comfort and rapid recovery from the immediate condition.

Also advantageously, the present formulations, methods and procedurescan also be adapted and arranged to anticipatorily treat before as aprecaution in case of an unanticipated or accident-related trauma thatmay occur, as a pre-exposure precautionary measure taken to reduce therisk of neuropathology in individuals who are about to enter into asituation or condition where there is a great likelihood of trauma,including such conditions as a dangerous military or law enforcementoperation or situation, an impending or underway bioterrorism or otherattack where neurotoxic chemicals or other agents have been or may havebeen released.

In a similar manner, the present formulations can be adapted andarranged to treat any damage, wound, insult, cut, laceration,concussion, lesion, abrasion, contusion, shock, strain, abruptacceleration, abrupt deceleration, explosion, percussion, metabolicevent that causes, results in, brings about, triggers or leads to or cantrigger or can lead to secondary injury or damage or change in structureor change in phenotype or change in gene expression or loss of functionor altered function or cell death of a nerve cell, a neural support cellor a neural support tissue, as well as to treat physical traumaincluding vehicle accidents, workplace accidents, sports accidents,falls, burns, radiation, battlefield injuries, concussive injuries,blast injuries, injuries from landmines, injuries from improvisedexplosive devices, penetrating injuries, non-penetrating injuries or theresult of any traumatic event that can injure, damage, modify, kill orotherwise change the phenotype, gene expression function of a nervecell, a neural support cell or a neural support tissue.

In addition, the present technology can be adapted and arranged to treatchemical trauma including alcohol overdose, drug abuse, stimulant drugs,carbon dioxide poisoning, lead poisoning, copper poisoning, acrylamideand related chemicals, overexposure to certain environmental chemicalssuch as copper or natural hazards such as insect and other animal venomtoxins, herbicides, insecticides, industrial toxic chemicals,bioterrorism chemicals and other chemicals that can injure, damage,modify, kill or otherwise change the phenotype, gene expression functionof a nerve cell, a neural support cell or a neural support tissue.

Thus, the many embodiments of the invention are adaptable andarrangeable to treat metabolic trauma including, as examples, hypoxia,ischemia, hypoxia, multiple sclerosis, shingles, diabetes, stroke,epileptic or other seizure, post-polio syndrome, HIV/AIDS peripheralneuropathy, subacute posttraumatic myelopathy, and other effects,syndromes and conditions following a type of trauma to the body that caninjure, damage, modify, kill or otherwise change the phenotype, geneexpression function of a nerve cell, a neural support cell or a neuralsupport tissue.

Other exemplary applications of the present technology include thoseadapted and arranged to treat trauma resulting from medical treatment ormedical procedure trauma including injections, surgery, amputation,implantation, laparoscopy, chemotherapy (for example but not exclusivelywith methotrexate, cisplatin, cytosine arabinose, carmustine, thiotepaamong others), radiation therapy, immunosuppressants (for exampletacrolimus) and the like, or during a medical procedure that can reduceor impede the blood supply for any period of time and the like.

Trauma from surgery includes, as examples, laparoscopy, amputation,mastectomy, cesarean section, cardiac surgery, hernia repair,cholecystectomy, joint replacement, thoracotomy, reparative surgery orany case, condition or situation where there is or might be detectableor undetectable cut, wound, injury or damage to nerves, nerve cells,neural support cells or neural support tissues that can injure, damage,modify, kill or otherwise change the phenotype, gene expression functionof a nerve cell, a neural support cell or a neural support tissue, aswell as to treat trauma including radiation, burns, hypoxia, cold, heator other trauma that can injure, damage, modify, kill or otherwisechange the phenotype, gene expression function of a nerve cell, a neuralsupport cell or a neural support tissue, and to treat any damage orinjury to a cell that is required for or promotes or facilitates thenormal function, health, survival, phenotype, gene expression andfunction of nerve cells including glial cells, microglia, myelin cells,satellite cells, astroglia, oligodendrocytes, Schwann cells, satellitecells, interstitial cells of Cajal and vascular endothelial cells, totreat any damage or injury to a tissue that supports or is required foror promotes or facilitates the normal function, health, survival,phenotype, gene expression, survival or function of nerve cells andneural support cells and includes the vasculature and microvasculatureto nerve cells and neural support cells in the central nervous systemand in the periphery, and to treat any neurotrophic mechanism orneurotrophic effect or neurotrophic action that encompass therapeuticstrategies intended to promote, facilitate or augment survival, health,function, recovery, proliferation, differentiation, growth, orregeneration of one or more cells or tissues, and includes anybiochemical, cellular, tissue or metabolic process that is activated bythe traumatic event or by the direct tissue damage from that event andthat leads to or can lead to restoration, recovery or repair of nerves,nerve cells, neural support cells or neural support tissue or thatprotects or restores health of nerves, nerve cells, neural support cellsor neural support tissues.

Scope of the Invention

The foregoing description sets forth various embodiments offormulations, methods, procedures and practices for reducing orpreventing the development, or the risk of development, ofneuropathology as a result of traumatic injury. Insofar as suchformulations, methods, procedures and practices contain one or morefunctions or operations, it will be understood by those within the artthat each formulation, method, procedure and practice can beimplemented, individually or collectively, within a wide range of manycombinations without undue experimentation.

A person having ordinary skill in the art will recognize that, in onesignificant aspect, the herein described formulations (e.g., anycombination of any two, any three or all four of gabapentin,progesterone, aprepitant and lithium), methods, and procedures andpractices, and the discussion accompanying them, are used as examplesfor the sake of conceptual clarity and that various methods, proceduresand practices are within the skill of those in the art. Consequently, asused herein, the specific exemplars set forth and the accompanyingdiscussion are intended to be representative of their more generalclasses. In general, use of any specific exemplar herein is alsointended to be representative of its class, and the non-inclusion ofsuch specific formulation components (e.g., gabapentin, progesterone,aprepitant and lithium), methods, and procedures and practices hereinshould not be taken as indicating that limitation is desired.

It is generally contemplated that the formulations according to theinventive subject matter will be formulated for administration to amammal, and especially to a human, having a condition that is responsiveto the administration of such a formulation. Therefore, wherecontemplated formulation compounds are administered in a pharmacologicalcomposition, it is understood that contemplated compounds can beformulated in admixture with pharmaceutically acceptable carriers. As anexample but not exclusively, contemplated compounds can be administeredorally as pharmacologically acceptable salts, or intravenously in aphysiological saline solution (e.g., buffered to a pH of about 7.2 to7.5). Conventional buffers such as phosphates, bicarbonates or citratescan be used for this purpose. Of course, one of ordinary skill in theart may modify the formulations within the teachings of the presentdisclosure to provide numerous formulations for a particular route ofadministration.

In particular, contemplated compounds may be modified to render themmore soluble in water or other vehicle that, for example, may be easilyaccomplished with minor modifications (e.g. salt formulation,esterification, etc.) that are well within the ordinary skill in theart. It is also well within the ordinary skill of the art to modify theroute of administration and dosage regimen of a particular compound orformulation in order to manage the pharmacokinetics of the presentcompounds for maximum beneficial effect in a patient or subject.

Also in particular, contemplated compounds may be prepared for deliveryin tablet, capsule, pill or solution form, including any form that candeliver a controlled release of these compounds.

Similarly, it should be appreciated that while some claims recitecomponents of formulations of invention embodiments, one of skill in theart will comprehend that other constituents, while pharmacologicallyinactive or inert in the context of the presently disclosed technology,might be a part of the formulation. Such inactive constituents include,as examples, excipients, binders, coatings, absorption enhancers,penetration enhancers, transport enhancers, stabilizers, chelators,buffers, carriers, clearance modifiers, emulsifying agents,antioxidants, preservatives, sugars, salts, cellulose, dyes, flavoringagents and any other inactive ingredients that are considered generallyrecognized as safe.

In certain pharmaceutical dosage forms, prodrug and derivative forms ofcontemplated compounds may be formed for various purposes, includingreduction of toxicity, increasing the organ or target cell specificity,etc. Among various prodrug and derivative forms, acylated (acetylated orother) derivatives, pyridine esters and various salt forms of thepresent compounds may be advantageous. One of ordinary skill in the artwill recognize how to readily modify the present compounds to prodrugand other forms to facilitate delivery of active compounds to a targetsite within the host organism or patient. One of ordinary skill in theart will also take advantage of favorable pharmacokinetic parameters ofthe prodrug and other forms, where applicable, in delivering the presentcompounds to a targeted site within the host organism, subject orpatient to maximize the intended effect of the formulation.

Similarly, it should be appreciated that contemplated compounds may alsobe metabolized to their biologically active form (e.g., viahydroxylation, glycolsylation, oxidation etc.), and all metabolites ofthe compounds herein are therefore specifically contemplated. Inaddition, contemplated compounds (and combinations thereof) may beadministered in combination with yet further antiviral and/orantibacterial agents. Suitable additional drugs therefore include butare not limited to various antibiotics (e.g., beta-lactam antibiotics,tetracycline antibiotics, oxazine antibiotics, etc.), various antiviralcompounds (e.g., polymerase inhibitors), and/or compounds that stimulatethe immune system.

With the presently disclosed technology described in detail herein, itis to be understood that the invention is not limited to the particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments, and is not intended to be limiting,since the scope of the presently disclosed technology will be limitedonly by the appended claims or by a fair reading of the application as awhole.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimit of that range and any other stated or intervening value in thatstated range is encompassed within embodiments of the invention. Theupper and lower limits of these smaller ranges may independently beincluded in the smaller ranges is also encompassed within embodiments ofthe invention, subject to any specifically excluded limit in the statedrange. Where the stated range includes one or both of the limits, rangesexcluding either or both of those included limits are also included inembodiments of the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which embodiments of this invention belongs. Although anymethods and materials similar or equivalent to those described hereincan also be used in the practice or testing of the presently disclosedtechnology, a limited number of the exemplary methods and materials aredescribed herein.

All publications mentioned herein are hereby incorporated by referenceto disclose and describe the methods and/or materials in connection withwhich the publications are cited, as well as the general background forthe inventive subject matter disclosed herein. The publicationsdiscussed herein are provided solely for their disclosure prior to thefiling date of the present application. Nothing herein is to beconstrued as an admission that the presently disclosed technology is notentitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided might be different from theactual publication dates, which may need to be independently confirmed.

The inventive technology described herein sometimes illustratesdifferent components contained within, or connected with, differentother components. It is to be understood that such descriptions orsubject matter are merely exemplary, and that in fact many otherdescriptions, examples, methods, procedures and practices can beimplemented which achieve the same functionality. In a conceptual sense,any arrangement of components to achieve the same functionality iseffectively “associated” or “coupled” such that the desiredfunctionality is achieved. Hence, any two or more methods, procedures orpractices herein combined to achieve a particular functionality can beseen as “associated with” each other such that the desired functionalityis achieved, irrespective of condition, event, injury, damage orpathology components. Likewise, any two or more components so associatedcan also be viewed as being “operably connected”, or “operably coupled”,to each other to achieve the desired functionality, and any two or morecomponents capable of being so associated can also be viewed as being“operably couplable”, to each other to achieve the desiredfunctionality. Specific examples of operably couplable include but arenot limited to, practices of embodiments of the invention required underdifferent conditions, practices of embodiments of invention requiringdifferent routes or methods of administration, practices of embodimentsof invention requiring repeated administration for varying periods oftime or logically interacting or logically interactable components toachieve the desired functionality.

In a general sense, those skilled in the art will recognize that thevarious aspects described herein which could be implemented,individually or collectively, by a wide range of methods, procedures orpractices, or any combination thereof, can be viewed as being composedof various types of “formulation.” Consequently, as used herein“formulation” includes, but is not limited to, two compounds selectedfrom gabapentin, progesterone, aprepitant and lithium, three compoundsselected from gabapentin, progesterone, aprepitant and lithium or allfour compounds selected from gabapentin, progesterone, aprepitant andlithium. Those having skill in the art will recognize that the subjectmatter described herein may be implemented in a method, procedure orpractice as described herein, or some combination thereof.

As examples, the formulations, methods, procedures or practices ofcertain embodiments of the invention include many combinations andpermutations thereof with respect to the nature of the individualformulations, and their relative methods, procedures or practices, canvary in operation by the relative methods, procedures or practices.

While particular aspects of the present subject matter described hereinhave been shown and described, it will be apparent to those skilled inthe art that, based upon the embodiments herein, changes andmodifications may be made without departing from the subject matterdescribed herein and its broader aspects and, therefore, the appendedclaims are to encompass within their scope all such changes andmodifications as are within the true spirit and scope of the subjectmatter described herein.

Those skilled in the art will recognize that it is common within the artto describe methods, procedures or practices in the fashion set forthherein, and thereafter use standard practices to integrate suchdescribed methods, processes or procedures to reduce or prevent thedevelopment or the risk of development of neuropathology as a result oftraumatic injury. That is, at least a portion of the methods, proceduresor practices described herein can be integrated into reducing orpreventing the development or the risk of development of neuropathologyas a result of traumatic injury via a reasonable amount ofexperimentation. Those having skill in the art will recognize thattypical methods, procedures or practices generally include thosedescribed herein. A typical method, procedure or practice may beimplemented utilizing any suitable commercially available instrument,tool or device, such as any typically found in a medical facility orhealth delivery context or venue, and available to those typicallyfamiliar with methods, procedures or practices generally applied bythose skilled in the art.

With respect to the use of substantially any plural or singular termsherein, those having skill in the art can translate from the plural tothe singular or from the singular to the plural as is appropriate to thecontext or application. The various singular/plural permutations are notexpressly set forth herein for sake of clarity.

Furthermore, it is to be understood that the invention is defined by theappended claims, and by the many claims that could be supported by thepresent specification. It will be understood by those within the artthat, in general, terms used herein, and especially in the appendedclaims (e.g., bodies of the appended claims) are generally intended as“open” terms (e.g., the term “including” should be interpreted as“including but not limited to,” the term “having” should be interpretedas “having at least,” the term “includes” should be interpreted as“includes but is not limited to,” etc.). It will be further understoodby those within the art that if a specific number of an introduced claimrecitation is intended, such an intent will be explicitly recited in theclaim, and in the absence of such recitation no such intent is present.For example, as an aid to understanding, the appended claims may containusage of the introductory phrases “at least one” and “one or more” tointroduce claim recitations. However, the use of such phrases should notbe construed to imply that the introduction of a claim recitation by theindefinite articles “a” or “an” limits any particular claim containingsuch introduced claim recitation to inventions containing only one suchrecitation, even when the same claim includes the introductory phrases“one or more” or “at least one” and indefinite articles such as “a” or“an” (e.g., “a” or “an” should typically be interpreted to mean “atleast one” or “one or more”); the same holds true for the use ofdefinite articles used to introduce claim recitations.

It will be further understood by those within the art that virtually anydisjunctive word or phrase presenting two or more alternative terms,whether in the description, claims, or practices, should be understoodto contemplate the possibilities of including one of the terms, eitherof the terms, or both terms. It is also to be understood that theterminology employed in the Detailed Description sections of thisapplication is for the purpose of describing particular embodiments. Itis also contemplated that any optional feature of the inventivevariations described herein may be set forth and claimed independently,or in combination with any one or more of the features described herein.Moreover, in interpreting the disclosure, all terms should beinterpreted in the broadest possible manner consistent with the contextof the disclosed technology. In particular, the terms “comprises” and“comprising” should be interpreted as referring to elements, components,or steps in a non-exclusive manner, indicating that the referencedelements, components, or steps may be present, or utilized, or combinedwith other elements, components, or steps that are not expresslyreferenced.

Thus, many specific compositions, procedures and methods of the present“Pharmaceutical Formulations For The Treatment And Prevention OfTrauma-Induced Neuropathology And Neurodegeneration” have been disclosedand exemplified. It should be apparent, however, to those skilled in theart that many more modifications besides those already described arepossible without departing from the inventive concepts herein, or fromthe spirit of the invention. The inventive subject matter, therefore, isnot to be restricted except in the spirit of the disclosure.

To assist in understanding the numerous embodiments of the invention,Table 1 provides some examples of dose ranges of drug categories forsome particular embodiments of the invention. As such, Table 1illustrates both the components of the 2-component, 3-component, and4-component formulation of the invention, and the numerous unspecifiedformulations, which also fall within the spirit and scope of theinvention.

TABLE 1 Dose Ranges of Drug Categories For Some Particular Embodimentsof The Invention More Most Drug Exemplary Acceptable PreferablePreferable Preferable category Compound Range (mg) Range (mg) Range (mg)Range (mg) A/A Gabapentin   5-9,600 50-4,800  100-2,400 200-600 A/APregabalin 0.5-2,400 15-1,200 25-600  50-150 A/A Valproic acid  25-8,400250-4,200   750-3,750 1,000-3,000 N/N Progesterone 0.05-1,200  5-600 40-450 100-305 N/N Methyl- 0.02-500   2-250  10-80  15-45 prednisolonesodium succinate N/N Medroxy- 0.001-400    0.5-200  1-50 2.5-7.5progesterone acetate N/K Aprepitant 0.05-750   5-375  20-250  40-120 N/KVestipitant 0.001-200    1-100  1-60  5-15 N/K Casopitant 0.005-1,000 0.5-500  10-300  50-150 L/L Lithium 0.5-3,600 30-1,800 100-900  200-600carbonate L/L Lithium citrate 0.01-2,400  10-1,200 50-900 200-600 L/LLithium chloride   3-3,600 30-1,800 100-900  20600

What is claimed is:
 1. A formulation for use in treatment to prevent thedevelopment, or the risk of development, of neuropathology andneurodegeneration sequelae associated with or caused by trauma orneurotrauma to a subject in need, or for the amelioration of the effectscaused by trauma to a subject in need, the formulation comprising anytwo or any three or all four biologically active compounds in amountsthat are pharmaceutically effective for each compound, respectively,when used in combination with the other biologically active compounds,the compounds being selected from a pharmaceutically effective amount ofany two, or any three, or all four of: A. at least one biologicallyactive compound selected from the group comprising anticonvulsants andantiepileptics; B, at least one biologically active compound selectedfrom the group comprising neurosteroids and neuroactive steroids; C, atleast one biologically active compound selected from the groupcomprising NK-1 receptor antagonists; and D, at least one biologicallyactive compound selected from the group comprising lithium containingand lithium-related compounds.
 2. The formulation of claim 1, whereinthe at least one anticonvulsant or antiepileptic agent is one or morefrom the group consisting of gabapentin, pregabalin, barbiturates (suchas phenobarbital, methylphenobarbital, metharbital, barbexaclone andother central nervous system depressants), benzodiazepines (such asclozepam, clonazepam, chlorazepate, diazepam, midazolam, lorazepam, andother hypnotic, anxiolytic, anticonvulsant, amnesic compounds), bromides(such as potassium bromide), carbamates (such as felbamate,fluorofelbamate), carboxamides (such as carbamazepine, oxcarbazepine,eslicarbazepine acetate), fatty acids (such as valproic acid, sodiumvalproate, divalproex sodium, vigabatrin, progabide,sec-butyl-propylacetamide), fructose derivatives (such as topiramate),hydantoins (such as ethotoin, phenytoin, mephenytoin, fosphentoin),oxazolidinediones (such as paramethadione, trimethadione, ethadione),propionates (such as beclamide), pyrimidinediones (such as primidone),pyrrolidines (such as rivaracetam, levetiracetam, seletracetam),succinimides (such as ethosuximide, phensuximide, mesuximide),sulfonamides (such as acetazolamide, sultiame, methazolamide,zonisamide), triazines (such as lamotrigine), ureas (such aspheneturide, phenacemide) and valproylamides (such as valpromide,valoctamide) and others known and unknown, as well as any homolog orderivative or compound acting on or through a receptor, an enzyme orother mechanism upon which an anticonvulsive/antiepileptic can act, aswell as any compound acting on or through mechanisms that would modifyor affect in any way pathways or processes affected by one or moreanticonvulsant/antiepileptic compounds, as well as any relatedslow-release compound.
 3. The formulation of claim 1, wherein the atleast one neurosteroid or neuroactive steroid is one or more compoundsselected from the group consisting of progesterone, progesteroneprodrugs, progesterone derivatives, progesterone analogues, and otherprogesterone compounds such as but not exclusive to medroxyprogesteroneacetate, megestrol acetate, 17alpha-hydroxyprogesterone,5alpha-dihydroxyprogesterone, 3alpha,5alpha-trihydroxyprogesterone,14b-hydroxy progesterone, 17alpha-hydroxyprogesterone caproate,16-methyl-17-benzoyloxypregnen-4-en-3,20-dione,hydroxylprogesterone-3-O-carboxymethyloxime,21-succinyloxy-6,19-epoxyprogesterone, 6,19-oxidoprogesterone,17-p-bromophenyl-carbamoyloxypregn-4-ene-3,20-dione,17-phenylcarbamoyl-oxypregn-4-ene-3,20-dione, 4-pregnene-3,20-dione,6,19-methanoprogesterone, 16,17-cyclohexano-4,5-dihydroprogesterone,nepapakistamine, vaganine D, Crinone, 18-oxo-18-vinylprogesterone,16,17-cyclopropanoprogesterone, caproxyprogesterone,21-hydroxy-6,19-oxidoprogesterone,17-acetoxy-9-fluoro-6-methylprogesterone, ZK 136798,3,17-dihydroxy-7-(4-methoxyphenyl)-androst-5-ene, 3,17-diacetate,progesterone-11HS-horseradish peroxidase,21-hydroxy-11,19-oxidopregn-4-ene-3,20-dione,21-hydroxy-6,19-oxidopregn-4-ene-3,20-dione, 4-cyanoprogesterone,11,19-oxidoprogesterone, 6-fluoroprogesterone,2-hydroxy-4-pregnene-3,20-dione, progesterone-3-(O-carboxymethyloxime)-horseradish peroxidase, progesterone-11-hemisuccinyl-bovine serumalbumin, pentarane B, pentarane A, progesterone 6-hemimaleate,progesterone 6-hemisuccinate, 7-(carboxyethylthio)progesterone,progesterone 3-(O-carboxymethyl)oxime-bovine serum albumin,18-ethynylprogesterone, 18-vinylprogesterone,6-methylprogesteron-17-pivalate, progesterone-11-bovine serum albumin,allylestriol, progesterone-3-ethanolimine,3,20-dioxopregn-4-ene-18′-carboxaldehyde cyclic18′-(1,2-ethandiylmercaptal), 18-ethylenedithioprogesterone,17-acetoxy-6,16-dimethylene-4-pregnene-3,20-dione,17-hydroxy-6-dehydroprogesterone,2′-methyl-16,17-cyclohexaneprogesterone, 21,21-dichloroprogesterone,hydroxyprogesterone hemisuccinate bovine serum albumintetramethylrhodamine isothiocyanate,11-progesteryl-2-carboxymethyltyramine-4-(10-methyl)acridinium-9-carboxylate,progesterone 12-succinyltyrosine methyl ester, progesterone11-succinyltyrosine methyl ester,11-progesteryl-2-succinoyltyramine-4-(10-methyl)acridinium-9-carboxylate,2-hydroxymethyleneprogesterone, 2-cyanoprogesterone,17-(phenylseleno)progesterone, 21-(phenylseleno)progesterone and othersknown and unknown, and include other neurosteroids or neuroactivesteroids such as, but not exclusive to neuroactive progestagens(including but not limited to pregnenolone(3beta-hydroxypregn-5-en-20-one), 17α-hydroxypregnenolone, progesterone,17α-hydroxyprogesterone, dehydroepiandrosterone, androstenedione,deoxycorticosterone, 11-deoxycortisol, 3 alpha-hydroxy-5alpha-pregnan-20-one (allopregnanolone), 3 alpha,21-dihydroxy-5alpha-pregnan-20-one (allotetrahydroDOC), neuroactive androgens(including but not limited to androstenedione (the precursor of3alpha,5alpha-A, or androsterone), androsterone(5alpha-androstan-3alpha-ol-17-one; 3alpha,5alpha-A),5alpha-dihydrotestosterone (5alpha-DHT) and its metabolite5alpha-androstane-3alpha,17beta-diol (3alpha,5alpha-Adiol),3α,17β-dihydroxy-5α-androstane, 3α-hydroxy-5α-androstan-17-one,3α-hydroxy-5β-androstan-17-one, androst-5-ene-3β,17β-diol,3β,17α-dihydroxy-pregn-5-en-20-one (17α-hydroxy-pregnenolone),3β-hydroxy-androst-5-en-17-one (dehydroepiandrosterone, DHEA),testosterone, androst-4-ene-3,17-dione (androstenedione), neuroactiveestrogens (including but not limited to estradiol, 17β-estradiol (βE2),17α-estradiol (αE2), estrone (E1) and estriol (E3), and phytoestrogens),neuroactive glucocorticoids (including but not limited to prednisolone),other neuroactive steroids metabolically downstream from these principalneuroactive steroids including but not limited to allopregnanolone,allotetrahydrodeoxycorticosterone (THDOC), and dehydroepiandrosterone(DHEA), additional neuroactive steroids including other derivatives suchas estradiol benzoate, neurosteroids and neuroactive steroids including,but not limited to, prednisolone, methylprednisolone, alphaxalone,alphadolone, hydroxydone, minaxolone, ganaxolone, deoxycorticosterone, 3alpha-hydroxy-5-alpha-pregnan-one (allopregnanolone), 3alpha,21-dihydroxy-5 alpha-pregnan-20-one (allotetrahydro), as well asmetabolites of neurosteroids and neuroactive steroids, and including anycorticoid, glucocorticoid, estrogen, estrogen compound, androgen orandrogen compound or any such compound acting on or through aprogesterone, corticosteroid, glucocorticoid, estrogen, androgen orother neurosteroid or neuroactive steroid receptor or through any othermechanism upon which progesterone, a corticosteroid, a glucocorticoid,an estrogen or other neurosteroid or neuroactive steroid does or canact, as well as any homolog or derivative or compound acting on orthrough mechanisms that would modify, modulate or affect in any waypathways or processes affected by progesterone, estrogen or anyneurosteroid or neuroactive steroid, as well as any related slow-releasecompound.
 4. The formulation of claim 1, wherein the at least one NK-1receptor antagonist is one or more from the group consisting ofaprepitant, fosaprepitant, casopitant, maropitant, vestipitant,CP-99,994, CP-122,721, MK 869, LY 303870, RPR 67580, RPR 100893, L758298, L 365260, L 733060, GR 205171, CGP 49823, CJ 11974, and othersknown and unknown, and any compound acting on or through the NK-1receptor or any other mechanism that involves activation or involvementof the NK-1 receptor or its synthesis, and other chemical entities knownand unknown, including any ligand or compound acting on or through anNK-1 receptor or other mechanism upon which substance P, an endogenousligand for the NK-1 receptor, does or can act, as well as any compoundacting on or through mechanisms that would modify or affect in any waypathways or processes affected by substance P or the NK-1 receptor, aswell as any related slow-release compound. Further, in view of theevidence that some ligands and compounds can act through or by NK-2 orNK-3 receptors, any ligand or homolog or derivative or compound actingon or through an NK-1 or NK-2 or NK-3 receptor, including receptorisoforms, or related mechanism as well as any ligand that occupies,activates or deactivates these receptors, is included in the presentlydisclosed technology.
 5. The formulation of claim 1, wherein the atleast one lithium-containing or lithium-related agent is one or morefrom the group consisting of lithium carbonate, lithium citrate, lithiumchloride, lithium bromatum and others known and unknown, as well as anycompound acting on or through a lithium receptor or other mechanism uponwhich lithium does or can act, as well as any homolog or derivative orcompound acting on or through mechanisms that would modify or affect inany way pathways or processes affected by lithium, as well as anyrelated slow-release compound.
 6. The formulation of claim 1, whereinthe formulation consists of any two or any three or all four of theanticonvulsant or antiepileptic, the neurosteroid or neuroactivesteroid, the NK-1 receptor antagonist and the lithium containing orlithium-related compound, and is formulated for first administrationwithin 24 hours after the trauma.
 7. The formulation of claim 1, whereinthe formulation consists of any two or any three or all four of theanticonvulsant or antiepileptic, the neurosteroid or neuroactivesteroid, the NK-1 receptor antagonist and the lithium containing orlithium-related agent, and is formulated for administration within 90minutes before an expected or potential trauma or before a possibletrauma, and wherein the formulation consisting of any two or any threeor all four of the anticonvulsant or antiepileptic, the neurosteroid orneuroactive steroid, the NK-1 receptor antagonist and the lithiumcontaining or lithium-related agent is formulated for administrationwithin 24 hours of the trauma.
 8. The formulation of claim 1, formulatedfor administration of as a tablet, a capsule, a pill, or an injectablesolution.
 9. The formulation of claim 1, formulated for administrationvia an oral, buccal, mucosal, parenteral, rectal, sub-cutaneous,transdermal, intravenous, intrathecal, intravaginal, nasal, nasalinhalation, pulmonary inhalation, iontophoresis through the skin,iontophoresis through mucosal or buccal membranes, dermal patch,epidural, intracranial, intrapharyngeal, sublingual, intra-articular,intramuscular or a subcutaneous route.
 10. The formulation of claim 1,wherein one or more of the compounds is in the form of one or more ofsalts, prodrugs, hydrates, derivatives or metabolites of the compounditself, analogues, homologues, compounds acting on or through mechanismsthat compounds can act on or through or compounds that modify, modulateor affect in any way pathways or processes affected by compounds orformulations of the invention and wherein the formulation is in such aform that it can be safely administered to, given to, or taken by, asubject, and may include other ingredients or substances such asexcipients, buffers, penetration enhancers, stabilizers, absorptionenhancers and carriers.
 11. The formulation of claim 1, wherein the atleast one anticonvulsant is gabapentin, pregabalin or valproic acid, ina form adapted and arranged for administration to a mammal in needthereof, wherein the gabapentin is provided in a dosage range of from5.0 to 9.600 mg, the pregabalin is provided in a dosage range of from0.5 to 2,400 mg and the valproic acid is provided in a dosage range offrom 25 to 4,800 mg.
 12. The formulation of claim 1, wherein the atleast one neurosteroid is progesterone, methylprednisolone, ormedroxyprogesterone acetate, in a form adapted and arranged foradministration to a mammal in need thereof, wherein the progesterone, isprovided in a dosage range of from 0.05 to 1,200 mg, themethylprednisolone, is provided in a dosage range of from 0.02 to 500 mgand the medroxyprogesterone acetate, is provided in a dosage range offrom 0.001 to 400 mg.
 13. The formulation of claim 1, wherein the atleast one NK-1 receptor antagonist is aprepitant, casopitant orvestipitant, in a form adapted and arranged for administration to amammal in need thereof, wherein the aprepitant, is provided in a dosagerange of from 0.05 to 750 mg, the vestipitant, is provided in a dosagerange of from 0.001 to 200 mg and the casopitant, is provided in adosage range of from 0.005 to 1,000 mg.
 14. The formulation of claim 1,wherein the at least one lithium-containing compound is lithiumcarbonate, lithium citrate or lithium chloride, in a form adapted andarranged for administration to a mammal in need thereof, wherein thelithium carbonate, is provided in a dosage range of from 0.5 to 3,600mg, the lithium citrate, is provided in a dosage range of from 0.01 to2,400 mg and the lithium chloride, is provided in a dosage range of from3.0 to 3,600 mg.
 15. The formulation of claim 1, adapted and arranged totreat one or more changes in cellular or tissue structure, function orhealth, occurring in one or more of the central nervous system,including the brain, the brainstem, the cerebellum and the spinal cord,and the periphery, including the enteric nervous system and theperipheral nervous system, wherein the changes include neuropathy,neuropathology, neurodegeneration and the effects of trauma, and can bedue to one or more neurotrophic and neuroprotective andneurodegenerative mechanisms, the changes resulting short-, medium- orlong-term from trauma, including Alzheimer's disease, Parkinson'sdisease and other degenerative disorders where trauma is a risk factor.16. The formulation of claim 1, adapted and arranged to treat one ormore selected from the group comprising physical trauma includingvehicle accidents, workplace accidents, sports accidents, falls, burns,radiation, battlefield injuries, concussive injuries, blast injuries,injuries from landmines, injuries from improvised explosive devices,penetrating injuries, non-penetrating injuries or the result of anytraumatic event that can injure, damage, modify, kill or otherwisechange the phenotype, gene expression function of a nerve cell, a neuralsupport cell or a neural support tissue, chemical trauma, metabolictrauma, medically-related trauma and other trauma, where injury ordamage is to at least one nerve, at least one nerve cell, at least oneneural support cell or at least one neural support tissue, whether inthe central nervous system or in the periphery, comprising chemicaltrauma including alcohol overdose, drug abuse, stimulant drugs, carbondioxide poisoning, lead poisoning, copper poisoning, acrylamide andrelated chemicals, overexposure to certain environmental chemicals suchas copper or natural hazards such as insect and other animal venomtoxins, herbicides, insecticides, industrial toxic chemicals,bioterrorism chemicals and other chemicals that can injure, damage,modify, kill or otherwise change the phenotype, gene expression functionof a nerve cell, a neural support cell or a neural support tissue,comprising metabolic trauma including hypoxia, ischemia, hypoxia,multiple sclerosis, shingles, diabetes, stroke, epileptic or otherseizure, post-polio syndrome, HIV/AIDS peripheral neuropathy, subacuteposttraumatic myelopathy, and other effects, syndromes and conditionsfollowing a type of trauma to the body that can injure, damage, modify,kill or otherwise change the phenotype, gene expression function of anerve cell, a neural support cell or a neural support tissue, comprisingtrauma resulting from medical treatment or medical procedure traumaincluding injections, surgery, amputation, implantation, laparoscopy,chemotherapy (for example but not exclusively with methotrexate,cisplatin, cytosine arabinose, carmustine, thiotepa among others),radiation therapy, immunosuppressants (for example tacrolimus) and thelike, or during a medical procedure that can reduce or impede the bloodsupply for any period of time and the like, where trauma from surgeryincludes, as examples, laparoscopy, amputation, mastectomy, cesareansection, cardiac surgery, hernia repair, cholecystectomy, jointreplacement, thoracotomy, reparative surgery or any case, condition orsituation where there is or might be detectable or undetectable cut,wound, injury or damage to nerves, nerve cells, neural support cells orneural support tissues that can injure, damage, modify, kill orotherwise change the phenotype, gene expression function of a nervecell, a neural support cell or a neural support tissue, and comprisingtrauma including radiation, burns, hypoxia, cold, heat or other traumathat can injure, damage, modify, kill or otherwise change the phenotype,gene expression function of a nerve cell, a neural support cell or aneural support tissue.
 17. The formulation of claim 1, adapted andarranged to treat brain, brainstem and cerebellum trauma comprising oneor more from the group comprising brain injury, ischemia of the centralnervous system, spinal cord trauma comprising one or more ofcompression, vertebral collapse, cutting wounds, puncture wounds, crushwounds, surgical or medical intervention, and ischemia resulting fromloss of blood, insufficient circulation from stoppage or slowing of theheart, or surgical interruption of the blood supply to the spinal cord,enteric nervous system trauma comprising one or more from the groupcomprising neurons, progenitor cells, glial cells and interstitial cellsof Cajal, cells of Auerbach's myenteric plexus and Meissner's submucosalplexus, as well as neural support cells and neural support tissues,including luminal, lamina propria and muscularis mucosal cells, as wellas endothelial cells of the vasculature, peripheral nerve traumacomprising one or more from the group comprising sensory nerves, motornerves, autonomic nerves, nerve cells, neural support cells, such asSchwann cells, myelin cells, satellite cells, as well as neural supporttissues such as the vasculature.
 18. The formulation of claim 1, adaptedand arranged to treat following trauma as an emergency treatment oftrauma as would be in the case of unanticipated or accident-relatedtrauma, taken as soon after trauma as possible that may prevent thedevelopment of neuropathology or the risk of development ofneuropathology including such conditions as motor vehicle accidents,battlefield injuries, sports injuries, toxic chemical spill and thelike, where evidence informs that there is a risk of damage to brain,spinal cord or peripheral nerve. Emergency treatment of neurotrauma isdifferent from emergency treatment of trauma, where immediate steps aretaken to prevent further injury, to stop bleeding, to stabilize thevictim and to take life-saving steps.
 19. The formulation of claim 1,adapted and arranged to treat before trauma as a precautionary treatmentin case of an unanticipated or accident-related trauma that may occur,as a pre-exposure precautionary measure taken to reduce the risk ofneuropathology in individuals who are about to enter into a situation orcondition where there is a great likelihood of trauma, including suchconditions as a dangerous military or law enforcement operation orsituation, an impending or underway bioterrorism or other attack whereneurotoxic chemicals or other agents have been or may have beenreleased.
 20. The formulation of claim 1, adapted and arranged to treatbefore trauma as would be in the case of anticipated, potential orpurposeful trauma, taken as a pre-exposure prophylaxis measure to reducethe risk of neuropathology in individuals who are about to undergoprocedures where there is a risk of trauma, including such conditions assurgery, chemotherapy, radiation therapy and the like, where evidenceinforms that there is a risk of damage to brain, brain stem, cerebellum,spinal cord, peripheral nerve and/or enteric nerve cells, and whereinprophylaxis of neurotrauma is different from pre- and post-surgicalcare, where steps are taken
 21. The formulation of claim 1, adapted andarranged to treat any damage, wound, insult, cut, laceration,concussion, lesion, abrasion, contusion, shock, strain, abruptacceleration, abrupt deceleration, explosion, percussion, metabolicevent that causes, results in, brings about, triggers or leads to or cantrigger or can lead to secondary injury or damage or change in structureor change in phenotype or change in gene expression or loss of functionor altered function or cell death of a nerve cell, a neural support cellor a neural support tissue, wherein the formulation is required for orpromotes or facilitates the normal function, health, survival,phenotype, gene expression and function of nerve cells including glialcells, microglia, myelin cells, satellite cells, astroglia,oligodendrocytes, Schwann cells, satellite cells, interstitial cells ofCajal and vascular endothelial cells or is required for or promotes orfacilitates the normal function, health, survival, phenotype, geneexpression, survival or function of nerve cells and neural support cellsand includes the vasculature and microvasculature to nerve cells andneural support cells in the central nervous system and in the periphery.22. The formulation of claim 1, adapted and arranged to treat bypromoting or facilitating any neurotrophic mechanism or neurotrophiceffect or neurotrophic action that encompass therapeutic strategiesintended to promote, facilitate or augment survival, health, function,recovery, proliferation, differentiation, growth, or regeneration of oneor more cells or tissues, and includes any biochemical, cellular, tissueor metabolic process that is activated by the traumatic event or by thedirect tissue damage from that event and that leads to or can lead torestoration, recovery or repair of nerves, nerve cells, neural supportcells or neural support tissue or that protects or restores health ofnerves, nerve cells, neural support cells or neural support tissues. 23.The formulation of claim 1, adapted and arranged to treat by inhibitingor slowing degenerative mechanisms involved in the progression ofsecondary injury or damage, apoptosis, necrosis, excitotoxicity, atrophyor cell death of one or more cells or tissues following the onset ofinsult or trauma and includes any biochemical, cellular, tissue ormetabolic process that is activated by the traumatic event or by thedirect tissue damage from that event and that leads to or can lead toloss of cell integrity, structure, phenotype, gene expression, functionor survival, or cell death. Such processes can or do lead to furtherdamage or injury to such cells and tissues, as a secondary injury ordamage.
 24. The formulation of claim 1, adapted and arranged to treatany damage, injury, harm, loss, change in structure, change inphenotype, change in gene expression or change in function or survivalof nerves, nerve cells, neural support cells or neural support tissuethat occurs after a traumatic event and develops over the seconds,minutes, hours, days, weeks or months following such an event. Secondaryinjury or secondary damage is usually considered to result frombiochemical cascades of cellular and metabolic processes that areactivated or triggered by the trauma-induced direct tissue damage.Secondary injury or secondary damage is usually considered to involveendogenous processes or biosynthetic pathways that govern, regulate orinfluence the structure, health, function or survival of nerves or nervecells, or cells upon which nerves or nerve cells depend to maintainhealth and function, such as neural support cells and neural supporttissues.